[PDF][PDF] Pdx1 maintains β cell identity and function by repressing an α cell program

T Gao, B McKenna, C Li, M Reichert, J Nguyen… - Cell metabolism, 2014 - cell.com
T Gao, B McKenna, C Li, M Reichert, J Nguyen, T Singh, C Yang, A Pannikar, N Doliba
Cell metabolism, 2014cell.com
Pdx1 is a homeobox-containing transcription factor that plays a key role in pancreatic
development and adult β cell function. In this study, we traced the fate of adult β cells after
Pdx1 deletion. As expected, β-cell-specific removal of Pdx1 resulted in severe
hyperglycemia within days. Surprisingly, a large fraction of Pdx1-deleted cells rapidly
acquired ultrastructural and physiological features of α cells, indicating that a robust cellular
reprogramming had occurred. Reprogrammed cells exhibited a global transcriptional shift …
Summary
Pdx1 is a homeobox-containing transcription factor that plays a key role in pancreatic development and adult β cell function. In this study, we traced the fate of adult β cells after Pdx1 deletion. As expected, β-cell-specific removal of Pdx1 resulted in severe hyperglycemia within days. Surprisingly, a large fraction of Pdx1-deleted cells rapidly acquired ultrastructural and physiological features of α cells, indicating that a robust cellular reprogramming had occurred. Reprogrammed cells exhibited a global transcriptional shift that included derepression of the α cell transcription factor MafB, resulting in a transcriptional profile that closely resembled that of α cells. These findings indicate that Pdx1 acts as a master regulator of β cell fate by simultaneously activating genes essential for β cell identity and repressing those associated with α cell identity. We discuss the significance of these findings in the context of the emerging notion that loss of β cell identity contributes to the pathogenesis of type 2 diabetes.
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